The benefits of inhaled therapy for treatment of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis have been recognized for many years. Direct administration of drug to the airways minimizes systemic side effects, provides maximum pulmonary specificity, and imparts a rapid onset of action.
Dry powder inhalers (DPIs) are becoming a leading device for delivery of therapeutics to the airways of patients. Currently, all marketed dry powder inhalation products are comprised of micronized drug (either agglomerated or blended) delivered from “passive” dry powder inhalers, DPIs. These inhalers are passive in the sense that they rely on the patient's inspiratory effort to disperse the powder into a respirable aerosol.
Despite their popularity and the pharmaceutical advantages over other inhaler types, passive dry powder inhalers typically have relatively poor performance with regard to consistency. In particular, DPIs emit different doses depending on how the patient uses the device, for example, the inhalation effort of the patient.
Also, the efficiency of DPIs can be quite poor. In one study comparing the performance of the two most widely prescribed DPIs, only between 6% and 21% of the dose emitted from the device was considered respirable. Improved performance for DPI devices is desperately needed from both clinical and product development standpoints. One promising approach to improving DPI performance is to modify the formulation rather than the device itself.
Conventional formulations for dry powder inhalation aerosols typically contain micronized drug of particle sizes small enough to enter the airways and be deposited in the lung. To make these highly cohesive and very fine particles dispersible, so called “carrier” particles are mixed with the drug particles. These coarse, and pharmaceutically inactive (or inert), carrier particles are found in nearly all dry powder inhaler products currently marketed. The carrier particles serve to increase the fluidization of the drug because the drug particles are normally too small to be influenced significantly by the airflow through the inhaler. The carrier particles thus improve the dose uniformity by acting as a diluent or bulking agent in the formulation.
Although these carrier particles, which are generally about 50-100 microns in size, improve the performance of dry powder aerosols, the performance of dry powder aerosols remains relatively poor. For instance, only approximately 30% of the drug in a typical dry powder aerosol formulation will be delivered to the target site, and often much less. Significant amounts of drug are not released from these conventional carrier particles and, due to the relatively large size of the carrier in relation to the drug, the drug is deposited in the throat and mouth of the patient where it may exert unwanted side effects.
A dry powder formulation is typically a binary mixture, consisting of micronized drug particles (aerodynamic diameter typically between 1 and 5 μm) and larger inert carrier particles (typically lactose monohydrate with 63-90 μm diameters). Drug particles experience cohesive forces with other drug particles and adhesive forces with carrier particles (predominately via van der Waals forces), and it is these interparticulate forces that must be overcome in order to effectively disperse the powder and increase lung deposition efficiency. The energy used to overcome the interparticulate forces is provided by the inspired breath of the patient as they use the inhaler. The aerodynamic forces entrain and de-aggregate the powder, though variations in the inhalation effort of the patient (e.g. such as those arising from fibrosis or obstruction of the airways) significantly affect the dispersion and deposition of the drug, producing the flow-rate dependency of the inhaler. Obviously, there is a need for improved dry powder formulations employing novel carrier particles to maximize the safety and efficacy profiles of current DPI inhalers.
The active pharmaceutical ingredient (API), also called a medicament, typically constitutes less than 5% of the formulation (% w/w), with lactose comprising the vast majority of the dose. The purpose of the carrier lactose is to prevent aggregation of the drug particles due to cohesive forces, primarily van der Waals forces arising from the instantaneous dipole moments between neighboring drug particles. Due to the small size of the drug particles these resulting cohesive forces are quite strong and not readily broken apart by the aerodynamic force provided by inhalation, producing aggregates that possess poor flow properties and end up depositing in the back of the throat. By employing a binary mixture, the drug adheres to the carriers particles instead and the larger size of the carrier particles allows them to be more easily entrained in the air stream produced when the patient inhales, carrying the API toward a mesh where the carrier particle collides; the force from the collision is often sufficient to detach the drug particles from the carrier, dispersing them in the airstream and allowing their deposition within the lung. Collisions with the inner walls of the inhaler may also be significant. However, a large fraction of API remains attached to carriers that do not collide effectively with the mesh, but instead are deflected, producing insufficient force to disperse the drug particles from its surface. API that does not dissociate from these carriers, along with drug adhered to carrier particles that slip through without any contact with the mesh, are deposited in the back of the throat via inertial impaction, often causing significant side effects in the throat.
Over the past twenty years considerable research into the optimal properties of DPI formulations has been conducted. DPI formulations have required larger inert carrier particles to be blended with the small micronized (<5 microns) drug particles to improve re-dispersion of the cohesive drug particles and reduce dosing variability. Without carrier particles, micronized drug remains aggregated and almost all is simply inhaled as far as the throat, where it is swallowed and never reaches the intended target. There have been many studies investigating these carrier particles yet modifications to their physiochemical properties (size, shape, crystallinity, surface fines, roughness, etc.) have failed to yield meaningful improvements in performance of DPIs. Moreover, these carrier particles (lactose in the US), are also responsible for batch to batch variability in DPI performance. One of the most commonly studied properties of carrier particles is carrier particle diameter. Over the course of 20 years, the general rule of thumb has been established that increasing carrier particle size leads to decreased DPI performance. FIG. 1 shows several examples from previous literature that indicated that increasing carrier particle size in DPI formulations leads to decreased performance.
Some conventional DPIs permit, and sometimes even intend, carrier particles to exit the inhaler. As a result, the carrier particles must be inert, and in the United States, the FDA restricts the carrier particle material to lactose. There is thus a need for advanced formulation technologies including alternative carrier particle materials that may be more judiciously chosen based on hygroscopic properties of the carrier (e.g., a desiccant material) and the surface interactions (e.g., acid or base character of the drug and carrier) between the carrier and the drug. As such, it may be desirable to provide a DPI that is completely void of carrier particles to allow for circumventing the FDA restriction of lactose as the carrier material.
Nasal delivery is used for treatment of a variety of illnesses such as allergic rhinitis, as well as for delivery of drugs for systemic or CNS action.
Both powder and liquid nasal delivery systems are currently on the market. The liquid delivery technologies have utilized spray pump derived technology or pressurized metered dose inhalers (pMDIs) for rapid jetting of the formulation into the nasal cavity. In general, nasal formulations are solution or suspension based requiring solvents or stabilizers. These are typically administered as sprays. Metered sprays and pump sprays have several disadvantages including:                Need for priming in order to secure “dose uniformity”        Complicated and expensive designs, involving many device parts in different materials.        The devices are difficult to manufacture        Formulations are less stable        Control over deposition site in nasal cavity is poor        Deposition of formulation is often concentrated to certain tissues and causes irritation on these areas while not treating other locations within the nasal cavity        Positioning of the device during use is critical and heavily dependent on patient use, therefore variability in dosing to target tissues is high        
DPI device technologies have been applied to nasal delivery predominantly for locally acting drugs. These formulations have notable advantages such as stability and dose delivery. These can be particularly advantageous for biological drugs and drugs requiring systemic plasma concentrations. Included in these systems are modified dry powder inhalers (developed for orally inhaled aerosol delivery) with a “nostril piece” instead of a “mouth piece”. Such devices are activated by nasal inhalation. These devices have also applied known concepts from DPI technology: reservoir dry powder with dose metering mechanisms—or capsule based devices needing piercing mechanisms and special loading procedures before use and after use. These device concepts inherit the same problems experienced when using DPIs for pulmonary delivery: complicated formulation, and high airflow resistance making it difficult to achieve sufficient nasal dose delivery.
To solve these device resistance problems, insufflators that “blow” the powder formulation of the drug into the nostril have been designed. In mechanical terms these devices are “bulky” and with limited portability, and impossible to operate with discretion. In addition, they suffer from the same in-use variability and regional deposition drawbacks of spray systems.